The etiology of many respiratory diseases has remained unclear in spite of direct attempts to determine factors that lead to pulmonary damage and loss of function. Asthma is a respiratory disorder affecting both children and adults. It is a multifactorial syndrome characterized by breathlessness, pulmonary constriction, airway hyperreactivity and mucous accumulation. It is often, but not always associated with allergies (extrinsic) or environmental stimuli, e.g., tobacco smoke.
The common physiological manifestation of asthma is the temporary constriction of the airways. Cellular infiltrates of the airway epithelium of symptomatic individuals include lymphocytes as well as myeloid granulocytes (Busse et al., Am. J. Respir. & Crit. Care Med., 152, 388 (1995)). Bronchoalveolar lavage (BAL) fluid or biopsies of lung tissue from affected individuals frequently show elevated levels of eosinophils, a myeloid leucocyte thought to play a role in host defense against parasitic infections.
Eosinophilia is characteristic of allergy and infection by helminths. One of the intriguing aspects of eosinophilia is its biological specificity, in which an increase in eosinophils can occur in the absence of increases in other leucocytes. In vitro data has suggested that the sequential action of interleukin-1(IL-1) and interleukin-3 (IL-3) or granulocyte stimulating factor (G-CSF) are necessary for eosinophil progenitor production while IL-5 is responsible only for the differentiation of progenitor cells into mature eosinophils (Sanderson et al., J. Exp. Med., 162, 60 (1985); Yamaguchi et al., J. Exp. Med., 167, 43 (1988); Clutterbuck et al., Blood, 75, 1774 (1990); Warren et al., J. Immunol., 140, 94 (1988)). IL-5 is expressed primarily by T cells, although other cell types may express this cytokine.
To define the role of IL-5 in vivo, Dent et al. (J. Exp. Med., 172, 1425 (1990)) made transgenic mice in which transcription of a genomic copy of the IL-5 gene was under the transcriptional regulatory influence of the dominant control region (DCR) of the gene encoding human CD2 (a T cell surface antigen). Although Dent et al. showed that serum IL-5 levels were elevated in transgenic mice (Tg5C2), because the CD2 enhancer element is only weakly active in mature peripheral T cells, the elevation in serum IL-5 levels was primarily due to thymocyte expression and not peripheral T cell expression. In contrast, serum IL-5 levels are elevated in parasite infested (Mesocestroides corti) or antigen challenged mice as a result of IL-5 expression by peripheral T cells. Moreover, despite the increase in serum IL-5 levels, the Tg5C2 mice showed no symptomatic effects of IL-5 overexpression other than a mild splenomegaly and an eosinophilia accompanying a 7-fold increase in white blood cell (WBC) count.
Tominaga et al. (J. Exp. Med., 173, 429 (1991)) disclose that transgenic mice in which a IL-5 cDNA was linked to the mouse metallothionein promoter (Tg-6 mice) demonstrated a peripheral eosinophilia with a 3-fold increase in total WBCs. Serum IL-5 levels in Tg-6 mice were 16,000 pg/ml. The predominant sites of IL-5 expression in these mice were the kidney and liver. These organ sites are not normally associated with the production of IL-5 and thus fail to mimic the necessary microenvironmental cues that occur in peripheral sites. Thus, the lack of significant physiological effects in these mice may be the result of ectopically produced IL-5.
Thus, a need exists for an animal model that constitutively expresses IL-5 in a tissue and/or cell-type specific fashion. Moreover, a need exists for an animal model that constitutively expresses IL-5 in thymocytes and peripheral T cells, so as to result in IL-5 induced pathologies.